The ability of humans to mount an effective immune response declines with age, leaving the elderly susceptible to infectious diseases and cancer. Moreover, vaccines tested in younger individuals are often ineffective in older people. Thus, as new vaccines are developed, it will be extremely important to test these formulations for efficacy in the elderly as well as in the young. While young nonhuman primates have been critical in testing vaccine efficacy for the general human population, a model using old nonhuman primates to assess vaccine protection for the elderly has not been established. We have begun to address this issue and in a recent study, found to our surprise that baboons, a nonhuman primate species used extensively in biomedical research, did not show immune senescence with aging. In fact, when old baboons (19-24 years old) were immunized with LcrV, a protective antigen from the plague bacterium, they responded even better than young animals (2 1/2 years old). Thus, although age-related loss in immune function has been observed in humans, rodents and a few nonhuman primate species, baboons appear to be unusual;they age without losing immune competence. Therefore, we propose to assess the effects of aging on immunity in four nonhuman primate species (baboons, rhesus macaques, chimpanzees, and marmosets). This is important for two reasons. First, in choosing an appropriate nonhuman primate for testing efficacy of vaccines in the elderly, it is critical to know that the model selected, like humans, becomes immune compromised with age. Second, if baboons are exceptional in that their immune systems age differently, they would provide a new model system for comparison to humans where aging does have profound effects on immunity. To address these critical issues, two aims will be undertaken. Aim I will test the effects of age on the ability of nonhuman primates to generate an effective immune response to three different protein antigens, LcrV and F1, from Y. pestis and tetanus, an immunogen used extensively in humans. Both B cell parameters [antibody titer, protective index, isotype, heterogeneity, affinity] and T cell parameters [subsets, circulating cytokines, fine specificity, in vitro proliferation and cytokine production] will be assessed. Furthermore, Aim II will examine thymic involution in these same nonhuman primate species to determine whether they, like rodents and humans, lose the potential for generating naive T cells with age. Completion of these aims will provide novel insights into immune response regulation in elderly nonhuman primates and will be critically important in choosing a NHP animal model for testing vaccines for use in the elderly. In addition, by correlating the ability to generate protective immunity with immune parameters, biomarkers that correlate with immune competence will be identified. PUBLIC HEALTH RELEVANCE: It has been well documented that immune responses are often less effective in older individuals resulting in an increased susceptibility to infectious diseases and decreased responses to immunization. The goal of this grant is to identify nonhuman primate models that most accurately reflect the immunosenescence seen in older humans and would serve as appropriate test subjects for development of vaccines to be used in the elderly.